In the pharmaceutical, biotechnology and even food, beverage and cosmetics industries, it is often desired to provide a processing system that is capable of handling fluids in a sterile manner. This is designed to prevent unwanted, often dangerous organisms, such as bacteria as well as environmental contaminants, such as dust, dirt and the like from entering into the process stream and/or end product. It would be desirable to have a completely sealed system but this is not always possible with the processes that take place in production.
There is a need for the introduction or removal of materials from the process stream in order to add components of the product, such as media or buffers to a bioreactor; withdraw samples from the process stream to check for microbial contamination, quality control, process control, etc.; and to fill the product into its final container such as vials, syringes, sealed boxes, bottles and the like.
Typically, the systems have been made of stainless steel and the system is exposed to live steam before use and then cleaned with chemicals such as caustic solutions after use to ensure that all contaminants are removed.
Steaming is the most effective means of sterilization. The use of steam in a set system is known as steaming in place or SIP. Saturated steam carries 200 times the BTU heat transfer capacity of heated air because of the latent heat released by the steam as it changes from vapor to liquid. However, several disadvantages exist with the use of steam. Any connections to or openings of the system made after the system has been steamed in place must be aseptic so as not to contaminate the system. Although this can be done using aseptic connectors this procedure increases the risk of contamination of the entire system. One typically uses alcohol wipes or an open flame to clean the components to be connected, (e.g. connecting a sample collection bag to a system after SIP has occurred) and thus minimize the risk of contamination.
Also, the high temperatures and pressure differentials of the steam make the selection of filter materials and components very difficult and limited and even then an accidental pressure differential at high temperatures can cause a filter, membrane or other non-steel component to fail.
Additionally, such systems that are reused need to undergo rigorous testing and validation to prove to the necessary authorities that the system is sterile before each use. The expense of validation as well as the cleaning regiment required is very high and very time consuming (typically taking 1 to 2 years for approval). In addition, some components are very difficult to adequately clean after use in preparation for their next use. Manufacturers are looking for ways to reduce both their costs and the time to market for their products. One possible approach is to adopt an all disposable system that is set up in a sterile fashion, used and then thrown away.
Biopharmaceutical manufacturers continue to prefer fully disposable filtration solutions due to reduced cleaning and capital equipment costs. Users will either purchase individual components and assemble them into the desired fluid flow path, or purchase preassembled flow paths, such as Millipore's Mobius® Solutions. Commonly these components or assemblies are pre-sterilized by the vendor using gamma irradiation. This reduces the bioburden and allows the user to achieve higher levels of aseptic assurance.
Although it is impossible to insure completely sterile assemblies, there are methods to reduce the risk of environmental contamination. Pre-sterilized assemblies are commonly sold with aseptic connectors, such as Millipore's Lynx® S2S, where the connections can be made in a validated sterile way. These kinds of connectors help control contamination from environment. Some customers order filter assemblies with connectors that can be directly sterilized by the customer, such as Millipore's Lynx® ST. This kind of connector acts as a valve and isolates the pre-sterilized filtration area from the environment. The methods of connection and the ability to insure sterility are of great importance and can be improved.
Disposable filter capsules are commonly sold pre-sterilized and packaged in the common aseptic double bag so the customer can manage bioburden by removing one bag at a time at various steps along the assembly process. However, such capsules cannot be used with non-disposable equipment because there is no simple means to sterilize both the reused and disposable components after they are assembled together. Although the filter membranes can survive steam-in-place (SIP) the capsule housing softens and may rupture during the high pressure and temperature exposure. Some manufacturers use high performance materials to withstand the extreme conditions, which incur additional product cost. Even with the use of high performance materials, the capsule must be aseptically installed.
In addition, in the use of a capsule filter such as by pharmaceutical manufacturers, it may become necessary to isolate a single filter form other filters, in order to retain sterility during installation, or to sterilize fluid pathways up to the capsule, for example. Also, a plurality of capsule filters is often used in parallel or in series, thereby necessitating their interconnection. An integral capsule connector that provides a parallel connection capability is advantageous in that it avoids external piping.
It therefore would be desirable to provide a pre-sterilized capsule that can be attached to existing reusable processing equipment, or to disposable equipment, and which can be sterilized such as by steaming-in-place while reducing environmental exposure. It also would be desirable to provide a filtration unit having an integral pre-sterilized capsule attached, as well as to provide a manifold assembly including one or more pre-sterilized capsules.